Novel anti-hypertensive compositions

ABSTRACT

Novel pharmaceutical compositions are disclosed which comprise a hypotensive agent and a phenyl hydrazino substituted propionic acid decarboxylase inhibitor. The compositions have enhanced anti-hypertensive activity.

BACKGROUND OF THE INVENTION

The present invention is directed to novel pharmaceutical compositions containing a hypotensive agent and a decarboxylase inhibitor.

The hypotensive agents of the present invention comprise agents, other than phenylalanine and reserpine type compounds, which are known to be effective in treating hypertension in humans. The decarboxylase inhibitor is encompassed in the class of hydrazino phenyl propionic acid compounds disclosed in U.S. Pat. No. 3,462,536; 3,830,827 and 3,781,415. Combinations of this hydrazino phenylpropionic acid type decarboxylase inhibitor with reserpine or phenylalanine type hypertensive agents are disclosed in Canadian Pat. No. 737,907 and U.S. Pat. No. 3,839,585.

It has now been discovered that the combination of the aforesaid non-phenylalanine, non-reserpine hypotensive agents with the hydrazino-phenyl propionic acid type decarboxylase inhibitors affords enhanced anti-hypertensive activity.

SUMMARY OF THE INVENTION

Novel pharmaceutical compositions comprising (a) a non-phenylalanine, non-reserpine hypotensive agent and (b) a D,L- or L-hydrazino-phenyl propionic acid decarboxylase inhibitor and a method of treating hypertensive animals.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of this invention is a hypotensive pharmaceutical composition comprising

A. a non-phenylalanine, non-reserpine hypotensive agent and

B. the L-isomer or racemic mixture (D,L-) of a hydrazino phenylpropionic acid decarboxylase inhibitor.

Preferred hypotensive agents are selected from the group consisting of (1) spironolacetone, hydralazine, trimethaphan camsylate, clonidine, guanethidine, thiazide diuretics, cryptenamine, pharmaceutically acceptable salts thereof and (2) sodium nitroprusside. A more preferred group of hypotensive agents includes hydralazine, clonidine, guanethidine, the thiazide diuretics and pharmaceutically acceptable salts thereof. A most preferred group of hypotensive agents is clonidine, hydralazine, guanethidine and their pharmaceutically acceptable salts.

The thiazide diuretics include the benzothiadiazine class of compounds having the basic ring structure ##STR1## Representative compounds are disclosed in U.S. Pat. No. 2,809,184; 2,937,169; 3,025,292; 3,164,588 and 3,043,840, and are incorporated herein by references.

The preferred thiazide compounds are chlorothiazide, hydrochlorothiazide, trichlormethizide, bendroflumethiazide, polythiazide, flumethiazide, and their pharmaceutically acceptable salts. Hydrochlorothiazide is a most preferred thiazide hypotensive agent.

Preferred decarboxylase inhibitors include the D,L-racemic mixture and the individual L-isomer of compounds having the formula: ##STR2## wherein R, R₁, R₂ and R₃ are independently selected from hydrogen and C₁ -C₄ alkyl such as methyl, t-butyl, isopropyl and the like. A more preferred decarboxylase inhibitor is the L-isomer and most preferred is the L-isomer of ##STR3## and its pharmaceutically acceptable salts. The monohydrate of IV is known as carbidopa.

Pharmaceutically acceptable salts include the salts of the various compounds with suitable organic or inorganic acids. Suitable organic acids are C₂ -C₂₄ carboxylic acids such as acetic acid, maleic acid, pamoic acid, succinic acid, citric acid, propionic acid, isethionic acid, oxalic acid, pivalic acid and the like. Suitable inorganic acids include the hydrohalides, e.g., HCl, HI, HBr, sulfuric acid, phosphoric acid and the like. The salts may also be alkali metal salts such as the sodium or potassium salt or the ammonium salt.

The compositions of the present invention may contain varying amounts of the hypotensive agent and decarboxylase inhibitor. In general, the weight ratio of hypotensive agent (a) to decarboxylase inhibitor (b) will be from about 4:1 to about 1:9000. A preferred weight ratio of (a):(b) is about 1:1 to about 1:1000 and a most preferred weight ratio is about 1:5 to about 1:500.

In treating hypertension, a sufficient amount of the present composition is administered to the hypertensive animal to produce the desired hypotensive effect, i.e., reduction in blood pressure. Effective dosages may vary and can range from about 0.2 mg/kg to about 1000 mg/kg per day. The composition may be given as a single daily dose or divided into several smaller doses during the course of the day.

The composition may be administered parenterally or orally. The dosage form used will depend on the mode of administration. The oral form may be a tablet, a liquid solution, dispersion, or emulsion, a capsule, or an encapsulated composition--while the parenteral dosage form will generally be a liquid solution, suspension or emulsion. The dosage forms generally will include conventional carriers, diluents, either solid or liquid, dyes etc. and will be prepared using applicable formulation procedures.

The compositions of the present invention are administered to hypertensive animals to effect reduction in blood pressure. The decarboxylase inhibitors are known to have no appreciable anti-hypertensive effect. When combined with the present hypotensive agents, however, the anti-hypertensive effect of the hypotensive agent is unexpectedly enhanced.

This enhancement of anti-hypertensive activity is demonstrated in vivo in spontaneously hypertensive (SH) rats. The procedure used is as follows:

The test animals used were conscious, male, SH rats weighing about 290 to about 340 grams. The arterial blood pressure was measured by a direct technique involving cannulation of the caudal artery. Initial blood pressure reading was recorded. The decarboxylase inhibitor was then administered intraperitoneally (i.p.) and about 5 minutes later the hypotensive agent was given, (i.p.). The blood pressure was then continuously recorded at 1/2 hour intervals for 24 hours.

The effect on blood pressure of the decarboxylase inhibitor and the hypotensive agent alone was also obtained by this method. The results of these tests for representative compositions of the present invention are in the following tables:

                                      Table 1                                      __________________________________________________________________________     Effects of guanethidine and hydrochlorothiazide, alone and in combination      with carbidopa, on the                                                         mean arterial pressure of conscious SH rats.                                   __________________________________________________________________________                   Dose    No.  Mean Arterial Pressure, mm Hg,                      Group         mg/kg   of   at hours after treatment                            __________________________________________________________________________     No.  Treatment                                                                               i.p.    Rats 0   1/2 1   2   4   8   12  18  24                  __________________________________________________________________________     1    Saline   2 mg/kg 9    168 170 170 170 166 164 166 166 164                 2    Carbidopa.sup.1                                                                         25      6    167 166 164 166 158 167 172 172 162                 3    Guanethidine.sup.2                                                                      0.078   6    179 178 177 177 174 180 180 177 178                 4    Guanethidine                                                                            0.312   5    174 167 168 171 171 174 170 170 166                 5    Guanethidine                                                                            0.625   4    176 180 180 178 172 179 173 174 176                 6    Guanethidine                                                                            1.25    4    171 143 163 150 150 154 147 155 162                 7    Guanethidine                                                                            5       4    174 131 133 132 140 157 155 163 162                 8    Carbidopa &                                                                             25      4    173 161 162 173 166 172 171 172 170                      Guanethidine                                                                            0.312                                                            9    Carbidopa &                                                                             25      6    173 157 140 137 137 144 152 147 149                      Guanethidine                                                                            0.625                                                            10   Carbidopa &                                                                             25      4    166 126 133 129 126 141 147 158 157                      Guanethidine                                                                            1.25                                                             11   Hydrochloro-                                                                            5       4    170 179 177 176 165 170 174 171 171                      thiazide.sup.3                                                            12   Hydrochloro-                                                                            20      4    164 161 159 161 159 163 152 151 149                      thiazide                                                                  13   Hydrochloro-                                                                            40      5    168 167 167 164 163 161 159 155 155                      thiazide                                                                  14   Hydrochloro-                                                                            80      5    169 152 160 142 145 145 141 141 140                      thiazide                                                                  15   Carbidopa &                                                                             25      4    170 169 161 159 156 158 152 154 152                      Hydrochloro-                                                                            5                                                                     thiazide                                                                  16   Carbidopa &                                                                             25      4    170 164 164 163 155 162 158 158 153                      Hydrochloro-                                                                            20                                                                    thiazide                                                                  17   Carbidopa &                                                                             25      5    179 181 170 162 148 160 158 162 161                      Hydrochloro-                                                                            40                                                                    thiazide                                                                  18   Carbidopa &                                                                             25      6    176 153 146 146 128 135 133 138 146                      Hydrochloro-                                                                            80                                                                    thiazide                                                                  __________________________________________________________________________      .sup.1 Dissolved in 1N HCl                                                     .sup.2 As Guanethidine sulfate dissolved in water                              .sup.3 Dissolved in 1N NaOH                                              

                                      Table 2                                      __________________________________________________________________________     Effect of hydralazine and clonidine, alone and in combination with             carbidopa, on the mean arterial                                                pressure of conscious SH rats.                                                 __________________________________________________________________________                   Dose    No.  Mean Arterial Pressure, mm Hg,                      Group         mg/kg   of   at hours after treatment                            __________________________________________________________________________     No.  Treatment                                                                               i.p.    Rats 0   1/2 1   2   4   8   12  18  24                  __________________________________________________________________________     1    Saline   2 ml/kg 9    168 170 170 170 166 164 166 166 164                 2    Carbidopa.sup.1                                                                         25      6    167 166 164 166 158 167 172 172 162                 3    Hydralazine.sup.2                                                                       0.03    3    167 169 165 173 172 166 168 171 173                 4    Hydralazine                                                                             0.125   4    170 166 165 166 171 174 168 168 167                 5    Hydralazine                                                                             0.25    4    180 159 166 172 170 172 175 176 169                 6    Hydralazine                                                                             0.5     9    164 128 138 146 152 161 160 160 159                 7    Hydralazine                                                                             1       4    180 120 127 157 157 178 176 177 176                 8    Hydralazine                                                                             2       5    169 120 126 135 144 152 156 154 162                 9    Carbidopa &                                                                             0.312   4    166 158 146 154 153 166 164 163 157                      Hydralazine                                                                             0.125                                                            10   Carbidopa &                                                                             1.25    4    163 155 142 145 151 156 147 147 151                      Hydralazine                                                                             0.125                                                            11   Carbidopa &                                                                             5       4    168 187 175 166 163 135 133 130 152                      Hydralazine                                                                             0.125                                                            12   Carbidopa &                                                                             25      4    174 163 157 144 138 152 160 163 160                      Hydralazine                                                                             0.03                                                             13   Carbidopa &                                                                             25      5    177 137 132 149 140 149 151 155 158                      Hydralazine                                                                             0.125                                                            14   Carbidopa &                                                                             25      4    173 146 147 158 158 159 164 164 170                      Hydralazine                                                                             0.25                                                             15   Carbidopa &                                                                             1.25    6    169 143 149 156 159 161 157 165 166                      Hydralazine                                                                             0.5                                                              16   Carbidopa &                                                                             5       6    172 134 129 143 150 152 152 149 154                      Hydralazine                                                                             0.5                                                              17   Carbidopa &                                                                             25      8    175 117 115 130 141 149 153 153 153                      Hydralazine                                                                             0.5                                                              18   Clonidine.sup.3                                                                         0.00075 4    170 171 171 170 169 166 172 161 170                 19   Clonidine                                                                               0.003   4    169 166 156 165 163 165 168 177 179                 20   Clonidine                                                                               0.0125  4    167 159 167 163 163 169 169 167 172                 21   Clonidine                                                                               0.025   6    168 148 147 149 151 154 151 149 150                 22   Clonidine                                                                               0.05    7    180 164 159 149 146 154 159 164 166                 23   Clonidine                                                                               0.2     3    173 164 147 152 150 148 152 157 162                 24   Carbidopa &                                                                             25      6    169 153 157 158 162 175 169 163 171                      Clonidine                                                                               0.00075                                                          25   Carbidopa &                                                                             25      6    168 134 141 146 150 148 151 152 162                      Clonidine                                                                               0.003                                                            26   Carbidopa &                                                                             25      5    166 144 139 143 154 161 167 170 164                      Clonidine                                                                               0.0125                                                           27   Carbidopa &                                                                             25      4    170 149 121 114 116 127 135 136 142                      Clonidine                                                                               0.05                                                             28   Carbidopa &                                                                             1.25    4    180 156 149 148 151 159 171 170 175                      Clonidine                                                                               0.05                                                             29   Carbidopa &                                                                             5       5    175 142 129 128 132 149 153 156 164                      Clonidine                                                                               0.05                                                             __________________________________________________________________________      .sup.1 Dissolved in 1N HCl                                                     .sup.2 As hydralazine . HCl Dissolved in water                                 .sup.3 As clonidine . HCl Dissolved in 1N HCl                            

The above data clearly shows the enhancement of antihypertensive properties of the non-reserpine, non-phenylalanine agent by the decarboxylase inhibitor.

Following are formulations of some representative dosage forms:

    ______________________________________                                         Tablet Formulation                                                             Clonidine hydrochloride                                                                              0.1      mg                                              Carbidopa             5.0      mg                                              Calcium phosphate     50.0     mg                                              Lactose               20.0     mg                                              Starch                10.0     mg                                              Magnesium sulfate     0.5      mg                                              Liquid Suspension                                                              Guanethidine sulfate  2.5      g                                               Carbidopa             2.5      g                                               Veegum HV             3.0      g                                               Methylparaben         1.0      g                                               Kaolin                10.0     g                                               Glycerin              250.0    g                                                ##STR4##                                                                      Injectable Solution                                                            Hydralazine hydrochloride                                                                            20       mg                                              Carbidopa .HCl        100      mg                                               ##STR5##                                                                      Capsule Formulation - I                                                        Hydrochlorothiazide   50       mg                                              Carbidopa             15       mg                                              Lactose               50       mg                                              Talc                  3        mg                                              Capsule Formulation - II                                                       Clonidine HCl         0.2      mg                                              Carbidopa             100.0    mg                                              Mannitol              98.0     mg                                              Stearic acid          1.0      mg                                              ______________________________________                                    

While the test results were obtained by i.p. administration of the two drugs of the present composition separately, the effect is demonstrative of the anti-hypertensive effect which would be obtained on administration, orally or parenterally, of the hypotensive agent and decarboxylase inhibitor either as a combination or individually and simultaneously. Another embodiment of this invention is a method of treating hypertensive animals by thus administering an anti-hypertensive amount of the aforesaid composition comprising the hypotensive agent and the decarboxylase inhibitor.

The term animals includes humans.

Claims to the invention follow. 

What is claimed is:
 1. A pharmaceutical composition for treating hypertension comprising effective amounts ofa. hydralazine or a pharmaceutically acceptable salt thereof and b. racemic mixture or L-isomer of a hydrazino phenyl propionic acid decarboxylase inhibitor,wherein the weight ratio of (a):(b) is 1:1 to about 1:1000.
 2. The pharmaceutical composition of claim 1 wherein said decarboxylase inhibitor has the formula: ##STR6##wherein R, R₁, R₂ and R₃ are independently selected from hydrogen and C₁ -C₄ -alkyl, and pharmaceutically acceptable salts thereof.
 3. The composition of claim 2 wherein R, R₂, and R₃ are hydrogen and R₁ is methyl and said (b) inhibitor is the L-isomer, substantially free of the D-isomer.
 4. The composition of claim 3 wherein said (a) is hydralazine hydrochloride.
 5. A method for treating hypertensive animals which comprises administration of 0.2 mg/kg to 1000 mg/kg per day of the claim 1 composition. 